Abstract
Osteoarthritis (OA), a most common and highly prevalent joint disease, is closely associated with dysregulated expression and modification of RXRα. However, the role of RXRα in the pathophysiology of OA remains unknown. The present study aimed to investigate whether RXRα modulator, such as K-80003 can treat OA. Experimental OA was induced by intra-articular injection of monosodium iodoacetate (MIA) in the knee joint of rats. Articular cartilage degeneration was assessed using Safranin-O and fast green staining. Synovial inflammation was measured using hematoxylin and eosin (H&E) staining and enzyme-linked immunosorbent assay (ELISA). Expressions of MMP-13, ADAMTS-4 and ERα in joints were analyzed by immunofluorescence staining. Western blot, RT-PCR and co-Immunoprecipitation (co-IP) were used to assess the effects of K-80003 on RXRα-ERα interaction. Retinoid X receptor α (RXRα) modulator K‐80003 prevented the degeneration of articular cartilage, reduced synovial inflammation, and alleviated osteoarthritic pain in rats. Furthermore, K-80003 markedly inhibited IL-1β‐induced p65 nuclear translocation and IκBα degradation, and down-regulate the expression of HIF-2α, proteinases (MMP9, MMP13, ADAMTS-4) and pro-inflammatory factors (IL-6 and TNFα) in primary chondrocytes. Additionally, knockdown of ERα with siRNA blocked these effects of K-80003 in chondrocytes. In conclusion, RXRα modulators K-80003 suppresses inflammatory and catabolic responses in OA, suggesting that targeting RXRα‐ERα interaction by RXRα modulators might be a novel therapeutic approach for OA treatment.
Highlights
Osteoarthritis (OA), a most common and highly prevalent joint disease, is closely associated with dysregulated expression and modification of Retinoid X receptor α (RXRα)
monosodium iodoacetate (MIA) induction low the expression of proteoglycan (Fig. 1B) and increased the number of MMP13 and ADAMTS-4 positive cells in cartilage in rats (Fig. 1C,D)
We reported that RXRα modulator K‐80003 prevented inflammatory and destructive responses in a rat model of osteoarthritis
Summary
Osteoarthritis (OA), a most common and highly prevalent joint disease, is closely associated with dysregulated expression and modification of RXRα. Retinoid X receptor α (RXRα) modulator K‐80003 prevented the degeneration of articular cartilage, reduced synovial inflammation, and alleviated osteoarthritic pain in rats. Nuclear factor-κB (NF-κB) pathways have been shown to be among the major contributors to OA pathology[3] Targeting these signaling pathway are beneficial in suppressing inflammatory and destructive responses in OA. Nonsteroidal anti-inflammatory drugs (NSAIDs) or a combination of steroid and hyaluronic acid (HA) can reduce joint pain and inflammation, a series of unwanted side effects restrict their application[4]. Anti-cytokine drugs have been proposed as promising therapeutic agents for OA These drugs can prevent the progression of joint structural changes, and some of them even have undergone clinical trials[2]. Our results suggested that K‐80003 prevented the degeneration of articular cartilage by interrupting RXRα-ERα interaction, subsequently enhancing ERα signaling and suppressing the NF‐κB pathway
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